Unknown

Dataset Information

0

A model of GAG/MIP-2/CXCR2 interfaces and its functional effects.


ABSTRACT: MIP-2/CXCL2 is a murine chemokine related to human chemokines that possesses the Glu-Leu-Arg (ELR) activation motif and activates CXCR2 for neutrophil chemotaxis. We determined the structure of MIP-2 to 1.9 Å resolution and created a model with its murine receptor CXCR2 based on the coordinates of human CXCR4. Chemokine-induced migration of cells through specific G-protein coupled receptors is regulated by glycosaminoglycans (GAGs) that oligomerize chemokines. MIP-2 GAG-binding residues were identified that interact with heparin disaccharide I-S by NMR spectroscopy. A model GAG/MIP-2/CXCR2 complex that supports a 2:2 complex between chemokine and receptor was created. Mutants of these disaccharide-binding residues were made and tested for heparin binding, in vitro neutrophil chemotaxis, and in vivo neutrophil recruitment to the mouse peritoneum and lung. The mutants have a 10-fold decrease in neutrophil chemotaxis in vitro. There is no difference in neutrophil recruitment between wild-type MIP-2 and mutants in the peritoneum, but all activity of the mutants is lost in the lung, supporting the concept that GAG regulation of chemokines is tissue-dependent.

SUBMITTER: Rajasekaran D 

PROVIDER: S-EPMC3511906 | BioStudies | 2012-01-01

REPOSITORIES: biostudies

Similar Datasets

1000-01-01 | S-EPMC3433787 | BioStudies
2012-01-01 | S-EPMC3290428 | BioStudies
2014-01-01 | S-EPMC4122422 | BioStudies
2020-01-01 | S-EPMC6943375 | BioStudies
2020-01-01 | S-EPMC7671035 | BioStudies
1000-01-01 | S-EPMC2684839 | BioStudies
2019-01-01 | S-EPMC6816105 | BioStudies
1000-01-01 | S-EPMC3218749 | BioStudies
2017-01-01 | S-EPMC5372524 | BioStudies
1000-01-01 | S-EPMC2898597 | BioStudies